Cancer Cell–Derived Matrisome Proteins Promote Metastasis in Pancreatic Ductal Adenocarcinoma
- 1 April 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 80 (7), 1461-1474
- https://doi.org/10.1158/0008-5472.can-19-2578
Abstract
The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor despite decades of effort. The abundant extracellular matrix (ECM) in PDAC comprises a major fraction of the tumor mass and plays various roles in promoting resistance to therapies. However, nonselective depletion of ECM has led to poor patient outcomes. Consistent with that observation, we previously showed that individual matrisome proteins derived from stromal cells correlate with either long or short patient survival. In marked contrast, those derived from cancer cells correlate strongly with poor survival. Here, we studied three cancer cell–derived matrisome proteins that are significantly overrepresented during PDAC progression, AGRN (agrin), SERPINB5 (serine protease inhibitor B5), and CSTB (cystatin B). Using both overexpression and knockdown experiments, we demonstrate that all three are promoters of PDAC metastasis. Furthermore, these proteins operate at different metastatic steps. AGRN promoted epithelial-to-mesenchymal transition in primary tumors, whereas SERPINB5 and CSTB enhanced late steps in the metastatic cascade by elevating invadopodia formation and in vivo extravasation. All three genes were associated with a poor prognosis in human patients and high levels of SERPINB5, secreted by cancer cells and deposited in the ECM, correlated with poor patient prognosis. This study provides strong evidence that cancer cell–derived matrisome proteins can be causal in promoting tumorigenesis and metastasis and lead to poor patient survival. Therefore, compared with the bulk matrix, mostly made by stromal cells, precise interventions targeting cancer cell–derived matrisome proteins, such as AGRN, SERPINB5, and CSTB, may represent preferred potential therapeutic targets. Significance: This study provides insights into the biological roles of cancer cell–derived matrisome proteins in PDAC and supports the notion that these proteins are protumorigenic and better therapeutic targets.Other Versions
Funding Information
- STARR Cancer Consortium
- Howard Hughes Medical Institute
- Lustgarten Foundation
- NCI Koch Institute (P30CA14051-45)
- Cold Spring Harbor (P30CA45508-27)
- Cold Spring Harbor
- NIH (5P30CA45508-27, 1U10CA180944-04, 1R01CA190092-04, 5P20CA192996-03, 1U01CA210240-01A1)
- DOD (W81XWH-13-PRCRP-IA)
- V Foundation
- MIT
- Swedish Research Council (537-2013-7277, 2017-01531)
- Kempe Foundations (JCK-1301)
- Swedish Society of Medicine (SLS-326921, SLS-250831, SLS- 175991, SLS-591551)
- Västerbotten (ALFVLL369081, VLL-643451)
- Cancer Research Foundation in Northern Sweden (AMP15-793, AMP17-877)
- Swedish Foundation for International Cooperation in Research and Higher Education (PT2015-6432)
- Knut and Alice Wallenberg Foundation Swedish Cancer Society (CAN 2017/332, CAN 2017/827)
- NCI Koch Institute (P30-CA14051)
- National Institute of Environmental Health Sciences (P30-ES002109)
- Ludwig Fund for Cancer Research the Koch Institute's Marble Center for Cancer Nanomedicine
- Howard Hughes Medical Institute
This publication has 74 references indexed in Scilit:
- Stefin B deficiency reduces tumor growth via sensitization of tumor cells to oxidative stress in a breast cancer modelOncogene, 2013
- Role of maspin in cancerClinical and Translational Medicine, 2013
- 61 Interactions Between Breast Cancer Stem Cells and their Niche Govern Metastatic Colonization of the LungEuropean Journal of Cancer, 2012
- Maspin: molecular mechanisms and therapeutic implicationsCancer and Metastasis Reviews, 2012
- The Matrisome: In Silico Definition and In Vivo Characterization by Proteomics of Normal and Tumor Extracellular MatricesMolecular & Cellular Proteomics, 2012
- SERPINB5 and AKAP12-- Expression and promoter methylation of metastasis suppressor genes in pancreatic ductal adenocarcinomaBMC Cancer, 2010
- Elucidating the Function of Secreted Maspin: Inhibiting Cathepsin D–Mediated Matrix DegradationCancer Research, 2007
- Invadopodia: Specialized Cell Structures for Cancer InvasionClinical & Experimental Metastasis, 2006
- Sensitization of stefin B-deficient thymocytes towards staurosporin-induced apoptosis is independent of cysteine cathepsinsFEBS Letters, 2005